The purpose of this study is to identify human genes predisposing to primary generalized osteoarthritis (PGOA), a form of osteoarthritis affecting the hands and other joints. DNA will be obtained from 200 multiplex families with radiographic OA. Multiple family members (average 4/ family) will be ascertained including affected and unaffected siblings in families with a minimum of two affected siblings for a total of 800 subjects from multiplex families. An additional 100 singleton cases (average 3 members/family)will be ascertained totaling an additional 300. It is anticipated that approximately 100 parents will also be involved for a grand total of 1200 study participants. Detailed family history and clinical information (including risk factor information) will be collected on all participating individuals. A database will be used to maintain all clinical (including x-rays of hands, hips, knees and lumbar spine) and family history data via the PEDIGENE data base system. We will perform a 10cM genomic screen in the first 200 multiplex families using a two-tiered approach for replication and follow-up. State of the art genetic analysis (both parametric as well as model-free analyses) will be employed. The initial marker(s) of interest as well as two additional flanking markers will be genotyped in the genomic screen (N=200) as well as in the follow- up data set (N=200). These studies represent linkage analysis using affected sib pairs. We will genotype the interesting regions as determined by the follow-up analyses with all known polymorphic markers in the area. No results are available as yet. Year 1 data has been collated and clinical and radiographic phenotype data are being reviewed and revised for initiation of large scale study to involve 1200 individuals (200 families) over the next three years. Once a potential susceptibility gene (s) is (are) identified we will examine the respective data for both gene/gene and gene/environment interactions incorporating the risk factor data collected as part of the clinical work-up of patients and family members. We anticipate that this first round of analyses has the potential to identify genes of both major and moderate effect in both OA. These studies represent the first step in defining the underlying etiology of this common familial disorder. Future analyses can include extensive association studies using SNPs localized throughout the genome. The data set that we will ascertain and sample in OA will leave us well-positioned to employ all methods both current and under development. Significance: New chondroprotective therapies are now being developed for OA, such as metalloproteinase inhibitors. As these therapeutic interventions come into clinical use, it will be beneficial to identify a population at high risk for developing OA in order to ameliorate the effects of this devastating and disabling disease early in the disease course. Those at greatest risk for developing early and severe osteoarthritis are likely to be those with genetic causes for OA. The ability to detect OA currently relies on measures, such as radiographs which detect late and irreversible disease. Thus, the ability to identify high risk individuals genetically would facilitate early interventions, primary prevention of the disease and treatment of preclinical OA when the disease is potentially reversible.